Secret of sleep science

• The National Sleep Foundation states that children need 10–11 hours of sleep a night... Sleep across the Night Lecture 3 The last lecture covered the different states of sleep, REM and

Course Guidebook

Professor H Craig Heller

Stanford University

Secrets of Sleep Science:

From Dreams to Disorders

Better Living

Topic

Health & WellnessSubtopic

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H Craig Heller, Ph.D

Lorry I Lokey/Business Wire Professor

of Biological Sciences and Human Biology

Stanford University

Professor Heller received his undergraduate

degree from Ursinus College and his Ph.D

in Biology from Yale University For two years, he was a postdoctoral fellow at Scripps Institution of Oceanography, and then he joined the faculty at Stanford University, where he has taught since 1972

Professor Heller’s research has ranged widely, including such topics as thermoregulation, hibernation, circadian rhythms, sleep, learning and memory, and human physical performance He is the coauthor of more than

200 peer-reviewed research papers His current focus is on the role of sleep and circadian rhythms in learning and memory as applied to the development

of therapies for the learning disabilities of Down syndrome and Alzheimer’s disease The other focus of Dr Heller’s laboratory is the development of technologies for the efficient regulation of heat into or out of the body His team is investigating many medical and nonmedical applications of this technology, including the protection of athletes from heat illness and the improvement of physical conditioning

Professor Heller has held many positions at Stanford University, including Chairman of Biology, Director of Human Biology, Chairman of the Academic Senate, and Associate Dean for Research Currently, he is the Director of the Wallenberg Network Initiative, which is a consortium that includes Stanford University and Lund and Umeå universities in Sweden This network supports diverse research projects that involve the application of information technologies in the neurosciences, social sciences, and humanities Beyond Stanford, Dr Heller is a member of the Defense Science Research Council, which he chaired for the past two years He also has served as Program Chair for the Associated Professional Sleep Societies

Virtually all Biology and Human Biology undergraduates at Stanford over the past three to four decades have learned physiology from Professor Heller In addition to his undergraduate core courses in neurobiology and physiology, he also has taught advanced courses in human physiology and in the neurobiology of sleep and circadian rhythms He has received the Walter

J Gores Award for excellence in teaching and the Kenneth M Cuthbertson Award for exceptional contributions to Stanford University

Professor Heller’s teaching in physiology extends far beyond Stanford

University He is a coauthor of a leading college textbook, Life: The

Science of Biology, which is in its 10th edition and has been translated into six foreign languages He is also a coauthor of a new biology textbook

titled Principles of Life Dr Heller has led several other biology education

projects, including HumBio, a multidisciplinary curriculum for the middle grades, and Virtual Labs, a set of interactive, computer-based instructional modules in physiology.■

We spend about one third of our lives sleeping, but scientists are

only beginning to understand how and why One thing, however,

is clear: Sleep is just as essential to life as nutrition and exercise

In fact, lack of sleep impairs performance, exacerbates psychological and psychiatric problems, and contributes to a host of illnesses And the consequences of too little sleep extend beyond the merely personal From automobile accidents to lost productivity at work to major disasters, such as

the Exxon Valdez oil spill, sleep deficits have levied a heavy toll on society

Next, we address the question of sleep in the wider animal kingdom, where

a variety of behaviors enable us to compare what might be sleep states in other species, including insects Two lectures follow on the brain’s circadian clock, which times most activities in the body, including when we sleep Rich in experimental detail, these lectures provide crucial information for understanding the effects of jet lag, shift work, and seasonal affective disorder The discussion of circadian rhythms also lays the foundation

Secrets of Sleep Science:

From Dreams to Disorders

in an effort to make sense of the complex neural networks that control sleep and all its manifestations The discussions of neuroanatomy, neurochemistry, and neurophysiology lead to lectures on narcolepsy and dreams We learn how basic animal research has led to greater understanding of sleep in humans and to more effective treatments for sleep disorders We also inquire into the possible functions of dreams and ask why amnesia for dreams might

be important to mental health

The lecture on dreams is followed by a group of lectures in which we explore the possible functions of human sleep Of particular interest are experimental studies that suggest a strong connection between sleep and learning and memory In addition to assessing the strengths and weaknesses of the various hypotheses that focus on sleep and the brain, we will examine the role that sleep has to play in maintaining the health of the rest of the body, including its effects on stress and blood sugar

Next, we turn to another group of lectures, where the focus is on sleep disorders, including insomnia, sleep apnea, and the bizarre—and sometimes quite dangerous—world of parasomnias Among the parasomnias we discuss are sleepwalking, night terrors, and REM sleep behavior disorder

We also investigate sudden infant death syndrome and post-traumatic stress disorder (PTSD) PTSD involves the common complaint of incessant, extreme nightmares It appears that the emotional memory of traumatic experiences can become amplified through dreams, which suggests a possible therapy for the disorder

The final lectures address possible therapies and treatments for sleep disorders, focusing especially on the behavioral options that are open to everyone Increasingly, behavioral modifications are being used to counter insomnia and improve sleep Our modern lives do not prepare us well for normal, healthy sleep Recognizing the factors that impair our sleep makes

it possible to systematically mitigate them Significant changes or sacrifices are not necessary—a surprisingly simple set of rules can solve most cases

of insomnia We close with a lecture on the future of sleep research and the questions it may be able to answer to improve sleep for us all ■

Lecture 1: Sweet Sleep—Essential for a Healthy Life

Sweet Sleep—Essential for a Healthy Life

Lecture 1

Sleep exerts a powerful influence over many aspects of our lives—

from our moods, to our cognitive abilities, to the functioning of the organs in our bodies Sleep is a fascinating study, and during the course of these lectures, you’ll gain insights into the research about it and explore the elusive mysteries that make sleep one of the greatest scientific challenges of our day

The Personal Sleep Debt

• In the absence of disease, there are three basic components

of a healthy lifestyle: nutrition, physical fitness, and sleep In comparison to a lack of exercise and nutrition, however, lack of sleep leads to serious consequences much more rapidly The health consequences of lack of exercise take years to develop A person can go days without food In contrast, a day of sleep deprivation, or several days of inadequate sleep, can be deadly

• Lack of sleep has effects on mood, on cognitive performance, and

on energy levels But the serious issue is that the sleepy person is extremely vulnerable to falling asleep under any circumstances This is not a problem if the sleepy person is in front of the TV—but when you mix sleepiness with driving or operating machinery, the result is a very high incidence of injury, disaster, and death

• Sleep is homeostatically regulated, which means that if you do not get the requisite amount of sleep, you develop a sleep debt And when you develop a sleep debt, your brain works very hard to force you to pay that debt back

• Furthermore, like credit card debt, the sleep debt is cumulative You may cut back on sleep a little bit on certain days and think that you can handle it—and maybe you can with the help of a little coffee—but that little sleep debt does not magically go away Small

sleep debts accumulate into large sleep debts that you eventually have to pay back

Sleep and Alcohol

• Falling asleep at the wheel contributes to an estimated 10,000 automobile deaths a year in the United States—which is most likely an underestimate If you ask anyone what he or she thinks is the leading cause of automobile accidents, most will reply drinking and driving, and that is where most of our public education, monitoring, and enforcement efforts are directed What few people recognize, however, is that there is a strong interaction between alcohol and sleep debt

• A modest dose of alcohol that has no measureable effect on a well-rested person will produce significant motor and cognitive impairment in a sleep-deprived person

• Further, the social situations associated with alcohol consumption are optimal for masking a sleep debt, so you are unaware of the danger When you are sleepy, stimulation keeps you awake Social situations that involve alcohol consumption usually occur in the evening when sleep debt is high, and they involve high levels

of wake-promoting stimulation—noise, conversation, physical activity But the drive home is the opposite situation: quiet, dark, warm, boring The onset of sleep is almost inevitable

The National Sleep Deficit

• Your personal sleep debt can have dire consequences for you But beyond that, our collective sleep debt has serious consequences for society as a whole—a national sleep deficit What is the size of the national sleep deficit? How much sleep do we need?

• The National Sleep Foundation states that children need 10–11 hours of sleep a night Teens need 8.5–9.5 hours, and adults need 7–9 hours

Lecture 1: Sweet Sleep—Essential for a Healthy Life

• Determining how much sleep we actually get is more complicated

In a recent National Health Interview Survey by the Centers for Disease Control and Prevention (CDC), 30 percent of adults reported getting fewer than 6 hours of sleep per night In another study, almost 70 percent of high school students reported getting fewer than 8 hours of sleep per night

• The problem is that these numbers are probably serious underestimates The reason is that many environmental conditions and sleep pathologies can compromise the quality of sleep and, therefore, contribute to sleep deprivation, even though the subjects are unaware of their problem

• To help us calculate the national sleep deficit, we can quantify daytime sleepiness by asking what percentage of people unintentionally fall asleep during the day In a 2009 CDC survey of the adult population in 12 states, about 40 percent reported falling asleep unintentionally at least once in the past month If the U.S population is 308 million, that means we’re talking about more than

120 million sleep-deprived people

• If we assume that their deficit averages 2 hours per night, we get

a deficit of more than 255 million hours per night Multiply that

number by 365 nights, and the annual national sleep deficit is approximately 90 billion hours

Long-Term Effects of Sleep Debt

• The consequences of sleep loss fall into two categories: immediate and long-term Over the long term, there are numerous health consequences of chronic patterns of insufficient sleep

• Obesity and weight gain have been linked to sleep debt in a number

of studies Getting less than 6 hours of sleep per night correlated with excess body mass, whereas subjects who got 8 hours per night had the lowest percent body fat

• Short sleep has also been linked to diabetes, which is the body’s inability to take up blood sugar and use it as metabolic fuel Juvenile or type 1 diabetes

is caused by a failure of the

pancreas gland to release

adequate amounts of the

hormone insulin Type 2 or

adult-onset diabetes results

when the cells of the body

are not able to respond to

the hormone insulin Many

studies have shown a strong

correlation between type

2 diabetes and short or

disturbed sleep

• In addition to obesity and

diabetes, studies have also

identified a correlation

between short sleep and hardening of the coronary arteries, which increases the risk of heart attack It is also well established that disturbed sleep increases the risk of high blood pressure, arrhythmia, heart attack, and stroke

• Researchers also have evidence that the ability to resist infectious diseases is impaired by short sleep Short sleepers are three times more likely to develop colds than comparable individuals who average 8 hours of sleep

• Further, there is strong evidence that short sleep can be a precipitating factor for the development of depression Individuals with insomnia have a tenfold higher risk of developing depression Similarly, a study of depressed patients revealed that they had a fivefold higher incidence of sleep-disordered breathing The study also found that treating the sleep-disordered breathing improves the symptoms of depression

Short sleepers are three times more likely to develop colds than comparable individuals who average

8 hours of sleep.

Lecture 1: Sweet Sleep—Essential for a Healthy Life

• Finally, in one large U.S national survey, individuals with sleep problems were 9 times more likely to have planned suicide and 7.5 times more likely to have attempted suicide Recent studies

of suicidal patients showed that treating their sleep disorders led

to healthier scores on clinical scales that measure suicidal thoughts and behaviors

Short-Term Effects of Sleep Debt

• The most obvious short-term effect of increased sleepiness is traffic and transportation accidents In 2007, it was estimated that

7 percent of all accidents and 18 percent of fatal accidents were fatigue related Yet driving while drowsy is increasingly common

in our 24/7 society

• For accidents involving heavy trucks, which are investigated by the National Transportation Safety Board (NTSB), the conclusion is that more than 50 percent of accidents involving heavy trucks are fatigue related

• NTSB also investigates all airline crashes, and here, the most common conclusion is that pilot fatigue due to long hours and irregular schedules is a dominant contributing factor

Performance, Productivity, and Major Disasters

• Performance, productivity, and safety in the workplace are greatly decreased by sleep-deprived workers In a study of the relationship between sleep and employee performance at four large U.S corporations, 15 percent of the workers met the strict clinical criteria for insomnia and insufficient sleep syndrome (ISS) For this group alone, the annual cost of their impairment in terms of lost performance, productivity, and safety was calculated to be approximately $3,000 per worker

• The U.S workforce is about 154 million If 15 percent are suffering from insomnia and ISS and costing employers $3,000 per year, the total loss is about $70 billion And if we further assume that

40 percent of all workers are at risk for ISS, the annual cost would

be an additional $142 billion That gives us a grand total of $212 billion lost in productivity, performance, and safety each year because of insufficient sleep

• A major disaster in a workplace situation is one of the most devastating consequences of the loss of sleep

○ But major disasters due to human error are not randomly distributed around the clock They are concentrated in the late-night and early-morning hours, when workers are sleepiest

○ Consider nuclear accidents: Chernobyl—1:23 am; Three Mile Island—4 am; Rancho Seco—4:14 am And then there are the infamous industrial accidents, such as the Union Carbide accident in Bhopal, which occurred at midnight, or the 1989

Exxon Valdez accident, which also occurred at midnight.

What Happens When We Sleep?

• Scientists can’t yet provide a full explanation for why we sleep But even in the absence of a definitive explanation, we do know that the purpose of sleep is related to certain requirements of the brain and nervous system

• Consider this: An animal is most vulnerable to predators when it

is asleep Why would evolution favor taking the brain offline and, therefore, giving up vigilance unless it were absolutely necessary for the brain itself?

• Activities of all the organs and organ systems of the body are very similar between quiet wake and sleep—except for the brain As we will see in a later lecture, amazing events happen in the brain over the course of a night’s sleep

• In this course, we’ll learn in detail what happens in our brains, all the way down to the cellular level, when we sleep We will also look at animal studies that explore various hypotheses about sleep function, such as its role in learning and memory

Lecture 1: Sweet Sleep—Essential for a Healthy Life

• In addition to looking at the relationship between sleep and the brain, we’ll examine such subjects as hibernation, dreaming, and the way sleep changes across the life span We will learn about sleep disorders, such as insomnia, sleep apnea, narcolepsy, and nightmares We’ll even find out how we can improve our sleep—in other words, how we can practice sleep hygiene

Barger, et al., “Impact of Extended-Duration Shifts on Medical Errors, Adverse Events, and Attentional Failures.”

Dement and Vaughn, The Promise of Sleep, chapters 3 and 9.

National Commission on Sleep Disorders Research, Wake Up America

1 Explain why you agree or disagree that we can compare the national sleep deficit to the national financial deficit

2 What is potentially more dangerous to your health, a week of excessive eating of high-calorie, high-cholesterol food or a week of short sleep? Why?

Suggested Reading

Questions to Consider

What Is Sleep?

Lecture 2

Sleep is truly bizarre and mysterious It presents us with phenomena

that have no obvious explanations but that challenge us to ask new questions and pursue elusive answers Normal sleep is a daily loss of consciousness that, if undisturbed by arousing stimuli, typically lasts 8 to 9 hours in humans This state of unconsciousness consists of two substates, as distinguished by the electroencephalograph (EEG) and other criteria: REM sleep and nonREM sleep This lecture will identify and describe the basic—

or defining—features of sleep, giving us a solid foundation for all the topics

we will discuss in this course

The EEG

• The science of sleep is relatively new Although scientific investigation of physiological processes, such as digestion, breathing, and circulation of the blood, goes back hundreds of years,

we didn’t get the first insights into the physiological mechanisms of sleep until 1924 The reason for this is that it was only then that the fundamental technology for studying the physiology of sleep was introduced

• That technology is the EEG, which gave us the ability to describe changes in the electrical activity in the brain in freely behaving, normal animals—and, of course, humans The EEG records patterns

of electrical activity that are created by the signals generated from large populations of neurons The first EEG technology was developed by German physiologist Hans Berger, and EEG technology has been the dominant tool in the field of sleep research ever since

• To get a better idea of what an EEG recording is, think of a lie detector apparatus, which records electrical events through time as deviations above (indicating positive) and below (indicating negative) a neutral center line The lie detector is also called a polygraph,

Lecture 2: What Is Sleep?

which means that it

can record multiple

variables at the

same time

• In the case of the

lie detector, these

variables could be

breathing rate, heart

rate, blood pressure,

and electrical

conductivity of the

skin, which indicates

sweating In the

case of the EEG,

the multiple variables being recorded are brain waves, electrical activity of muscles, eye movements, and sometimes heart and breathing rates These recordings used to be done by pen and ink on

a moving paper chart, but today, these lines appear on a computer screen

• Berger’s EEG machine revealed that there were two distinct patterns

of EEG activity that seemed to differentiate wake and sleep

○ During sleep, the pattern was mostly slow, high-amplitude waves, and during wakefulness, the pattern was fast and low-amplitude waves We refer to the EEG pattern during sleep

as synchronized, and we refer to the EEG pattern during our waking state as desynchronized

○ The synchronized pattern indicates that large populations of neurons are firing together in a slow, rhythmic pattern, and the desynchronized pattern reflects the fact that the awake brain is doing many unrelated things simultaneously

We can think of an EEG as describing the topography of electrical activity in the brain.

Sleep and Different Regions of the Brain

• In the 1940s, the EEG helped scientists investigate what parts of the brain were responsible for the switching between wake and sleep

○ It was known, largely through the treatment of soldiers who sustained injuries to the brain during battle, that if the wound was in the lower brain stem area, where the spinal cord emerges from the brain, the patient would be paralyzed but would have normal cycles of sleep and wake However, if the wounds were

in the upper part of the brain stem, the patient would most likely be in a permanent coma

○ From this, scientists concluded that signals from the brain stem area were necessary to bring the higher parts of the brain—the cerebral cortex—into a state of wake and maintain it in that state

• Two physiologists—the American Horace Magoun and the Italian Giuseppe Moruzzi—discovered that electrical stimulation of certain regions of the brain stem was effective in switching the synchronized EEG pattern to a desynchronized pattern

○ These areas did not correspond to any direct sensory or motor pathways responsible for communication between the brain and the rest of the body

○ Moruzzi and Magoun proposed that a region within the brain stem was responsible for maintaining the cerebral cortex in the state of wake They called this region the reticular activating system

• Around the same time, a Swiss physiologist—Walter Hess—discovered a brain region that did the reverse When stimulated,

it actually put cats to sleep and induced the synchronized EEG pattern This region was at the very anterior end of the brain stem in

a structure called the thalamus, which is an important way station for information coming up the neural axis to the cortex

Lecture 2: What Is Sleep?

REM and NonREM Sleep

• In the early 1950s, soon after the work of Moruzzi, Magoun, and Hess, a physiologist at the University of Chicago, Nathaniel Kleitman, applied both the EEG and EOG (electrooculogram, used to study eye movements) to study subjects over entire nights

of sleep

• Kleitman and a graduate student, Eugene Aserinsky, discovered a previously unrecognized phenomenon: rapid eye movements during sleep Unlike the slow, rolling eye movements that were recorded

by the EOG during most of sleep, there were stretches of time during sleep when the eye movements were fast and jerky, causing spikes in the EOG These episodes had a fairly regular pattern and typically occurred four or five times over the course of a night

• Soon thereafter, another student of Kleitman, William Dement, pursued the fact that these bouts of rapid eye movements correlated with a return of the EEG to a desynchronized pattern Since a desynchronized EEG pattern is associated with the waking state, it was quite remarkable to find this pattern during sleep

• The discoveries of Kleitman, Aserinsky, and Dement led to the categorization of sleep into two states: REM (rapid eye movement) sleep and nonREM sleep Sometimes REM sleep is referred to as desynchronized sleep, or active sleep NonREM sleep, on the other hand, is sometimes referred to as synchronized sleep, slow-wave sleep, or quiet sleep

• The Chicago group made another important discovery during their all-night EEG recordings If they woke the subjects when the EEG was in the synchronized or slow-wave pattern and asked them about their dreams, most subjects could not recall a dream or had only a vague recollection that they were dreaming

• In contrast, when the subjects were awakened during the REM episodes, they mostly reported vivid, active, and bizarre dreams Hence, REM sleep became known as dreaming sleep We now

know that dreaming occurs in nonREM sleep as well, but it is of

a different nature—less vivid, less dramatic, less emotional The extreme nature of dreams during REM sleep remains an important feature of this state of sleep

Muscle Atonia in REM Sleep

• There is another important feature of REM sleep that distinguishes

it both from the waking state and from nonREM sleep: muscle atonia, which means loss of muscle tone During REM sleep, muscle tone disappears When we are in REM sleep, we are essentially paralyzed The motor neurons that go to our muscles and cause them to contract are inhibited; they are shut down

• If this paralysis did not occur, we would act out our dreams Most people have experienced a consequence of this muscle paralysis in their dreams

○ Have you ever had a dream in which you had to run—you had

to get away—but you just could not move, or you were moving

as if your feet were mired in cement?

○ Normally, when you run, your brain gets feedback from your muscles that signals the fact you are running But in a dream, when your muscles are paralyzed, that feedback does not exist, and the sensation of running is absent

○ Thus, we can characterize nonREM sleep as a quiescent brain

in a moveable body and REM sleep as an active brain in a paralyzed body

• In fascinating experiments done at the University of Pennsylvania

by Adrian Morrison and Joan Hendricks, the parts of the brain stem responsible for the inhibition of motor neurons during REM were destroyed in cats by creating lesions in their brains Days after, the sleep patterns of the lesioned cats were studied They went to sleep normally and showed no differences in their nonREM sleep, but at the transition from nonREM to REM sleep, their heads perked up

as if they were paying attention to something, rather than dropping

Lecture 2: What Is Sleep?

• In a later lecture, we will discuss human situations in which motor inhibition is relaxed during REM sleep and the converse, when REM paralysis extends beyond the transition from REM to wake We will also discuss sleepwalking, which occurs during nonREM sleep

• Measuring all the various characteristics of sleep that we touched on

in this lecture helps us to diagnose and study sleep disorders, which are many Also, investigations into the mechanisms underlying these characteristics of sleep lead to the discovery of clues that can give us deeper understanding of sleep mechanisms and sleep functions As a first step, in the next lecture, we will take a closer look at how sleep is organized across the night and at how sleep deprivation influences the quality and quantity of restorative sleep

Benbadis, “Normal Sleep EEG.”

Dement, “Knocking on Kleitman’s Door.”

Gottesmann, “The Golden Age of Rapid Eye Movement Sleep Discoveries.”

1 Explain the experiments of Moruzzi and Magoun and those of Hess What is their significance?

2 Compare the distinguishing features of wake, nonREM sleep, and REM sleep

Suggested Reading

Questions to Consider

Sleep across the Night

Lecture 3

The last lecture covered the different states of sleep, REM and nonREM

This lecture discusses how these states relate to each other and how they might change over the normal sleep phase of the daily cycle We’ll put to use these tools used by sleep researchers: electroencephalogram (EEG), electrooculogram (EOG), and electromyogram (EMG) The lecture will also answer these questions: How long do individual episodes of REM and nonREM sleep last? Does the expression of these states change across the night? How do the sleep states relate to the duration of prior wakefulness?

Three Stages of NonREM Sleep

• Let’s consider a sleep study that involves recording each subject’s EEG, EMG, and EOG activity during an all-night sleep session

○ Preceding sleep, there is usually a time of relaxed wakefulness

or drowsiness During this period, the EEG changes from the fast, desynchronized wave pattern of alert wakefulness to a slower, more regular wave pattern at a frequency of 8–12 Hz (Hz refers to the number of waves, or cycles, that occur each second.) These slow, regular waves in the 8–12 Hz frequency range that characterize a relaxed, drowsy state are called alpha waves

○ The EOG indicates that slow eye movements are beginning

to occur The sleep-study subject has now entered stage 1 nonREM sleep During the descent into sleep, stage 1 nonREM lasts only a few minutes

• Next, the subject goes into stage 2 nonREM sleep During stage 2, the frequency of the EEG waves continues to slow down even as the

Lecture 3: Sleep across the Night

amplitude of the waves increases However, stage 2 nonREM sleep features occasional bursts of higher-frequency oscillations that are called sleep spindles Another component of stage 2 nonREM sleep

is K-complexes, which are very high amplitude spikes Neither eye movements nor dreaming occurs A person is easily awoken from stage 2

• As the subject’s sleep deepens, the EEG slows even more and shows the high-amplitude, slow waves that are the hallmark of deep sleep,

or stage 3 nonREM sleep Stage 3 sleep is also sometimes referred

to as slow-wave sleep because the EEG shows a dominance of slow waves in the band of 0.5–4.5 Hz Waves in this frequency band are called delta waves Rolling eye movements occur during stage

3 sleep

Sleep Cycles

• After about an hour of nonREM sleep, sleep lightens as the subject comes up from stage 3 to briefly pass through stages 2 and 1

○ As the EEG amplitude declines, the wave form gets faster Now, the EMG, which had been very quiet, falls even lower, and the EOG, which had displayed slow, rolling eye movements, shows periodic spikes as the eyes dart back and forth under the closed eyelids

○ The subject’s heart rate and breathing rate had been very regular during nonREM sleep, but now, they become somewhat irregular This is the first episode of REM sleep, and it will last about 10–20 minutes before the rapid eye movements cease, muscle tone increases, and the EEG again begins to slow

• The subject has gone through one full sequence of nonREM and REM sleep This is called a sleep cycle

○ The second episode of nonREM sleep progresses much like the first, and after about an hour, the EEG again returns rapidly through stages 2 and 1 to another episode of REM sleep

○ This second REM episode lasts longer than the first—about

30 minutes The third episode of nonREM sleep includes less stage 3 nonREM sleep, perhaps none Again, after about an hour, there is a return to REM sleep, and that third bout of REM

is usually even longer than the second—about 45 minutes

○ Overall, these sleep cycles (nonREM and REM sleep) average about 90 minutes After the last episode of REM sleep, the subject awakes That is typical; we almost always awake in the morning from the last episode of REM sleep

• Sleep researchers use a computer program and a graphic representation, called a hypnogram, of the changes in arousal states over the sleep phase Time is on the horizontal axis, and arousal state is on the vertical axis In comparing the hypnograms of all the subjects, we do see individual differences, but overall the hypnograms are remarkably similar In other words, the structure or architecture of human sleep is the same for nearly everyone

What Is the Function of Sleep?

• The function of sleep qualifies as one of the great unanswered questions of science We have to assume that sleep is restorative—but restorative of what? The most general answer to that question

is that sleep restores something that is depleted during wakeful activity If we can identify some aspect of sleep that has a clear quantitative relationship with duration of prior wakeful activity, understanding the mechanisms of that relationship might give us clues about the function or functions of sleep

• Essential physiological functions of the body are regulated That means they can be slowed down or sped up to meet the needs of the body and to maintain the state of the body in a fairly constant condition This maintenance of a constant internal condition is called homeostasis—a key concept in physiology

• To maintain homeostasis, a regulatory system needs information

It has to know what the optimal condition is, and it has to know

Lecture 3: Sleep across the Night

how far from optimal the current situation is This comparison produces an error message, used by the regulatory system to drive the responses that will get the body back to homeostatic balance

If we can find some aspect of sleep that appears to be regulated

in response to such perturbations as prolonged wakefulness, that aspect of sleep and the

information used to

regulate it should lead

us to answers about the

functions of sleep

• To find out how

sleep changes after

long periods of

wakefulness, we need

a mathematical tool

to analyze our EEG

data That tool, called

Fourier analysis, makes

it possible to describe

the EEG wave form quantitatively Fourier analysis enables us to determine how sine waves of certain frequencies contribute to the complex wave forms of sleep

• The EEG of stage 3 nonREM sleep has most of its power in the slow frequencies, and the EEG of REM sleep has more of its power

in faster frequencies If we compare the first bout of nonREM sleep with subsequent bouts of nonREM sleep, we find that there is a progressive decline in power in the slow frequencies This seems to indicate a process that reflects a high need at the beginning of sleep and a gradual decline as sleep continues across the night

• The slow-wave band that is so dominant during nonREM sleep is called the delta band, and the bump that is seen in REM sleep is called the theta band

declines across subsequent nonREM episodes If this is true, then we should be able to manipulate the magnitude of the delta power by controlling the duration of wakefulness prior to the onset of sleep

• We saw in the experiment that there was more stage 3 sleep early

in the night—the time of deepest sleep We also quantified this as greater delta power or slow-wave activity early in the night Thus, the tentative hypothesis is that delta power reflects sleep intensity

• What happens to delta power when we have been awake for a longer time—when we have been sleep deprived? It increases In fact, there is a very clear relationship between the duration of prior wake and the delta power during subsequent sleep In all cases, the delta power declines over the night, but it starts at a higher level early in the night Thus, we can pay back a sleep deficit in sleep intensity, as well as in sleep amount

Process S

• In a sleep experiment, subjects were kept awake for varying amounts of time and then released to sleep The interesting result was that the level of delta power at sleep onset was a function of how long the subject had been awake The decline in delta power had about the same rate in all subjects These and many other experiments have led to the concept of a “process S.” Process S

Lecture 3: Sleep across the Night

builds up during wake and is discharged during sleep If we could identify the physical factor responsible for process S, we could possibly gain insight about the actual function of nonREM sleep

• The main change that is seen in REM sleep in response to sleep deprivation is increased time spent in REM sleep Thus, the sleep following an extended period of wakefulness is characterized by longer REM sleep bouts

○ The increased time spent in REM following sleep deprivation can actually push off the nonREM recovery, and thus, total sleep recovery may take more than one or two nights of extended sleep

○ The relationships between sleep deprivation and the nature of recovery sleep are important because they provide clues that

we can pursue in our search for the functions of sleep

• It is reasonable to hypothesize that whatever the function of sleep is, it is at the cellular level After all, all energy processes, all biosynthesis processes, and all bioelectrical processes are carried out by cells What cellular processes are responsible for the generation of slow waves in the EEG? In a later lecture, we will explore this lead as a possible way of discovering a function

of sleep

• For our next lecture, however, we will describe the characteristics

of sleep and ask how these aspects of sleep change across the life cycle from the newborn to the elderly

Borbely, Tobler, and Hanagasioglu, “Effect of Sleep Deprivation on Sleep and EEG Power Spectra in the Rat.”

Suggested Reading

1 Explain the statement that the EEG is a complex mixture of sine waves Which sine waves would you expect to predominate in REM sleep and

in deep nonREM sleep?

2 What change is seen in sleep after a prolonged period of wake?

Questions to Consider

Lecture 4: Sleep across the Life Span

Sleep across the Life Span

Lecture 4

In the first weeks of life, a newborn sleeps about 16 hours a day, and that

sleep is about equally divided between REM and nonREM sleep The daily amount of nonREM sleep stays about the same until adolescence, but the amount of REM sleep steadily declines By puberty, REM sleep makes up 25–30 percent of total sleep time, and by young adulthood, it is 20–25 percent of total sleep time Throughout adulthood and into old age, the total daily sleep time gradually decreases, but the percent of REM and nonREM remains about the same This lecture addresses the biological bases for these changes and their possible consequences

The Timing of Sleep

• Sleep in the newborn is distributed around the clock (creating serious sleep disruption and deprivation in the parents) By about

2 to 4 months of age, the infant shows a tendency to sleep more

at night than during the day and will occasionally sleep for a continuous 5 or 6 hours

○ About 60 percent of 6-month-old babies sleep through the night, which reaches 80 percent by 9 months of age

○ Of course, infants continue to have sleep bouts during the day

By 6 months of age, this is usually down to two daytime naps, and by the time they are 12–18 months old, naps are down to one per day The pattern of a daily nap usually continues until about 5 years of age

• Probably the most critical change in the timing of sleep occurs at puberty What has only recently been established experimentally

is a biological cause of delayed sleep time that occurs at the time

of puberty

○ The multiple sleep latency test (MSLT) shows that there is a mechanism or process in the brain that opposes sleepiness This

process involves the ability of our brains to generate internally

a biological rhythm called a circadian rhythm

○ Circadian rhythms are common to virtually all organisms on earth, and they are characterized by the fact that even under absolutely constant environmental conditions, they have a period that is about a day long

• Our circadian rhythms modulate all sorts of biochemical, physiological, and behavioral activities of our bodies, including sleep and wake One function of circadian rhythm is clock-dependent alerting

○ The circadian rhythm generates an opponent process that resists the effects of the sleep need that builds up during wakefulness, causing sleepiness In the evening, when we have accumulated the most sleep need, clock-dependent alerting pushes back on the need to sleep and sustains our alertness

○ When this clock-dependent alerting fades, sleep need takes over, and it becomes very difficult to stay awake

The sleep debt accumulated by adolescents can lead to strong negative

consequences for mood, cognitive performance, and health.

Lecture 4: Sleep across the Life Span

• Extensive sleep studies led by Dr Mary Carskadon at Brown University have shown that at the time of puberty, the phase relationships between the two opponent processes—sleep need and clock-dependent alerting—change Because of this change in phase relationships of the opponent processes, many adolescents accumulate considerable sleep debt

Sleep Regulation

• Developmentally, over the life span, nonREM sleep emerges from undifferentiated brain activity earlier than does REM sleep

○ Such a conclusion would have evolutionary implications as

to which sleep state is more primitive, and it could also have implications about sleep function How do the two states of sleep relate to each other?

○ One idea we will discuss later is that wakefulness generates the need for nonREM sleep, and the expression of nonREM sleep generates the need for REM sleep If that idea is correct,

it would make no sense for REM sleep to develop before nonREM sleep

• Earlier, we discussed the interesting relationship between duration

of wake and the subsequent expression of EEG slow-wave activity during sleep When does this relationship appear during development? At what age does wake produce a need for sleep? And when does sleep serve a restorative function necessary for maintenance of wake?

• An animal experiment can help answer these questions

○ Neonatal rats cannot stay awake for very long At 12 days of age,

a short period of sleep deprivation by gentle handling induces

a strong sleep response But that response is in the duration of quiet/nonREM sleep, with no change in slow-wave activity

○ Suddenly, however, when they are 23 days old, the nature

of the response to sleep deprivation in rats changes from an

increase in duration of sleep to an increase in slow-wave activity or delta power

○ The ability of the neonatal rat to resist a sleep debt and to recover from that debt is quite minimal, which could be part of the reason for the large amount of sleep in newborns

The Effects of Aging on Sleep

• Let’s go to the other end of the life span Whereas in the old, about 20 percent of total sleep time is deep stage 3 nonREM sleep, it has declined to only about 3 percent in midlife (age 50)

25-year-• There’s little further decrease in stage 3 nonREM sleep as individuals reach advanced ages, but the total duration of sleep decreases by about 28 minutes per decade Also, sleep structure changes with age: It becomes more fragmented

• Even without specific sleep disorders, the ability to sustain continuous sleep is lost as we get older Sleep problems in older adults frequently go undiagnosed and untreated because the assumption is that worsened sleep is a normal aspect of aging To

a certain degree this is true, but treatment for any medical disorder that compromises sleep can improve sleep and the quality of life significantly

• A major factor is lack of physical exercise Increased activity during the day consolidates wakefulness and promotes better sleep

Lecture 4: Sleep across the Life Span

○ These brief arousals may be extremely frequent—200 to 300

a night—but extremely short, and the person may be totally unaware of them

○ In the morning, the individual may think that he or she had

a full 8 or 9 hours of sleep but does not feel refreshed and experiences extreme daytime sleepiness

• Another sleep disorder that disrupts sleep is restless legs and periodic limb movements Restless legs is the uncontrollable urge to move legs while falling off to sleep or during awakenings at night Periodic limb movements are uncontrollable jerkings of feet, legs, or sometimes arms during sleep The incidence of periodic limb movements is about 5 percent in adults up to age 50, but the incidence increases to more than 40 percent in individuals over age 65

Sleep and Longevity

• The average daily sleep amount in those over 65 or 70 is less than

6 hours The common knowledge is that 8 hours of sleep per night

is optimal, and less than that results in sleep debt For this reason, many older individuals worry about their short sleep and wonder if

it compromises their health

• There are also many individuals, described as long sleepers, who get more than 9 hours of sleep per night; this raises the question of whether one can get too much sleep and whether that contributes to poor health

• Many studies have been done to investigate the relationship between sleep duration and longevity These are mostly large-population epidemiological studies over long periods of time The populations

in these studies are mostly elderly, because the investigators want

to make connections between the information they gather and the eventual mortality statistics of the participants, and they don’t want

to wait 30 or 40 years to get their results

• The surprising finding is that higher risks of mortality are associated with both short sleep and with long sleep The lowest risks of mortality are associated with subjective sleep times around 6.5–7.5 hours Given the fact that subjective estimates of sleep are generally high, that means that the sleep duration associated with lowest risk

of mortality is considerably lower than 8 hours, which is generally considered to be optimal

• One recent study, led by Dr Dan Kripke at the University of California, San Diego, eliminated the subjectivity of estimating sleep time by using wrist actimetry to measure sleep time objectively Wrist actimetry is a reliable way to obtain data on sleep without doing overnight EEG/EMG measurements Kripke and colleagues reported the surprising result that the minimal mortality risk category was individuals who sleep between 5 and 6.5 hours

a night Higher mortality was seen in those who slept less than 5 hours and more than 7 hours per night

• We have said quite a bit already about some of the health issues associated with short sleep Long sleep is another issue What about long sleep could increase your risk of mortality? There are a number of possibilities, but there is no clear answer

• We will have much more to say about specific sleep problems throughout the rest of this course, but in the next lecture, we will turn back to studies of animal sleep

Frank and Heller, “Development of REM and Slow Wave Sleep in the Rat.”Kripke, et al., “Mortality Related to Actigraphic Long and Short Sleep.”Ohayon, et al., “Meta-Analysis of Quantitative Sleep Parameters from Childhood to Old Age in Healthy Individuals.”

Suggested Reading

1 Explain the multiple sleep latency test and what it shows.

2 How would you explain to a school board that elementary school students should be bused to school before middle school and high school students?

Questions to Consider

Who in the World Sleeps?

Lecture 5

If you have a pet dog or cat, you know that it spends a great deal of time

sleeping But what about sleep in birds, or lizards, or fruit flies? Do these animals sleep as we do? If so, why do they sleep? A quick survey of nature tells us that daily cycles of rest and activity are virtually universal in the world of multicellular animals This is not surprising, given the fact that our planet has rotated on its axis once a day since long before life evolved Daily cycles of light and dark, wet and dry, cold and hot are ever-present factors in the lives of organisms on earth

Basic Characteristics of Sleep

• The problem we face in studying patterns of rest and activity in the animal kingdom is that scientifically, we define sleep by characteristic patterns of brain activity, as measured by the EEG This methodology works fine for all mammals and for birds, but it fails as a tool for studying the physiology of rest in all other animals

• It’s also true that the EEGs of mammals and birds do not tell us anything about the underlying functions of sleep—they are only markers of different brain states A way to solve the problem is to establish a different set of biomarkers of sleep in mammals and birds and apply these criteria to other species—that is, to establish non-EEG indices of sleep

Lecture 5: Who in the W

Sleep in Invertebrates

• Recently, sleep researchers have begun to discuss invertebrate rest states as sleep The impetus for this change in acceptance of sleep

in nonmammals and birds was the amazing progress in studying the

fruit fly: Drosophila

• Around 2000, several papers appeared in the literature producing evidence that rest in fruit flies satisfied all the behavioral criteria for sleep

○ In each of these studies, researchers showed that the fruit flies had a rest state characterized by stereotyped posture and increased arousal thresholds

○ Also, the flies tended to isolate themselves from the activity of other flies in their environment before they went into this state

○ When the flies were deprived of this rest state for several hours,

it resulted in a subsequent increase in rest once the deprivation protocol ended